Submissions for variant NM_001199799.2(ILDR1):c.461C>T (p.Ser154Leu)

gnomAD frequency: 0.00057  dbSNP: rs115649165

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150843	SCV000198389	uncertain significance	not specified	2013-07-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ser154Leu varia nt in ILDR1 has not been reported individuals with hearing loss, but has been i dentified in 0.1% (10/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs115649165). Alth ough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not prov ide strong support for or against an impact to the protein. In summary, the cli nical significance of this variant cannot be determined with certainty; however, based its presence in the general population, we lean towards a more likely ben ign role.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375403	SCV001571884	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Supporting, BP4_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355013	SCV002302143	uncertain significance	not provided	2022-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 154 of the ILDR1 protein (p.Ser154Leu). This variant is present in population databases (rs115649165, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ILDR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 163702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001355013	SCV002552590	uncertain significance	not provided	2022-07-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002516029	SCV003699139	uncertain significance	Inborn genetic diseases	2021-08-16	criteria provided, single submitter	clinical testing	The c.461C>T (p.S154L) alteration is located in exon 4 (coding exon 4) of the ILDR1 gene. This alteration results from a C to T substitution at nucleotide position 461, causing the serine (S) at amino acid position 154 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355013	SCV001549767	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ILDR1 p.Ser154Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs115649165), ClinVar (variant is classified as a VUS by the Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine) and in LOVD 3.0 (variant is listed as VUS). The variant was also identified in control databases in 125 of 282676 chromosomes at a frequency of 0.000442 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 102 of 129062 chromosomes (freq: 0.00079), Other in 5 of 7222 chromosomes (freq: 0.000692), Latino in 9 of 35438 chromosomes (freq: 0.000254), African in 6 of 24904 chromosomes (freq: 0.000241) and European (Finnish) in 3 of 25112 chromosomes (freq: 0.00012); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ser154 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.